The present invention relates to compounds that are useful as modulators of the progesterone receptor, their preparation and use thereof.
Intracellular receptors (IR) form a class of structurally related gene regulators known as “ligand dependent transcription factors”. The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).
The natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as PR ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell's DNA. Once bound to the DNA the complex modulates the production of mRNA and the protein encoded by that gene.
A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist. Conversely, a compound which inhibits the effect of the hormone is an antagonist.
PR agonists (natural and synthetic) are known to play an important role in the health of women. PR agonists are used in birth control formulations, either along or in the presence of an ER agonist. ER agonists are used to treat the symptoms of menopause, but have been associated with a proliferative effect on the uterus which can lead to an increased risk of uterine cancers. Co-administration of a PR agonist reduces/ablates that risk.
PR antagonists can also be used in contraception. In this context they can be administered alone, in combination with a PR agonist, or in combination with a partial ER antagonist such as tamoxifen.
PR antagonists can also be useful for the treatment of hormone dependent breast cancers as well as uterine and ovarian cancers. PR antagonists can also be useful for the treatment of non-malignant chronic conditions such as uterine fibroids and endometriosis.
PR antagonists can also be useful in hormone replacement therapy for post menopausal patients in combination with a partial ER antagonist such as tamoxifen.
PR antagonists, such as mifepristone and onapristone, have been shown to be effective in a model of hormone dependent prostate cancer, which can indicate their utility in the treatment of this condition in men.
What are needed are other compounds which function as PR modulators, including PR agonists or antagonists.